PROJECT SUMMARY/ABSTRACT Modern drug discovery typically relies on chemical synthesis of organic small molecules, which are tailored to effect specified biological responses while retaining good bioavailability. In order for these efforts to succeed, robust methods for accessing structurally diverse candidates are necessary. Despite evidence that increased saturation and stereochemical complexity increase the probability that a drug candidate will reach the clinic, screening libraries heavily over-represent ?flat? molecules due to the maturity of cross-coupling methods for C(sp2)?C(sp2) bond formation. In order to improve the success rate of drug-development efforts, new methods for the stereocontrolled construction of sp3-rich structural motifs from readily available starting materials are essential. The proposed work seeks to address this need through the development of catalyst-controlled, mechanism-driven strategies for regio- and stereoselective construction of alicyclic building blocks from commodity chemicals using highly modular, nontoxic, Earth-abundant iron catalysts. Low-valent iron complexes bearing redox-active ligands are potent catalysts for olefin?diene coupling reactions. While catalysts affording excellent chemo-, regio-, and diastereoselectivity in [2+2]-cycloadditions have been identified empirically, development of robust selectivity models has lagged. Preliminary mechanistic evidence suggests that [2+2], [4+2], and hydrovinylation reactions proceed via formation of a common metallocyclic intermediate with multiple competing pathways for subsequent breakdown. Thus, Aim 1 will be directed toward the development of quantitative and predictive models for chemo-, regio-, and diastereoselectivity in iron- catalyzed cycloaddition reactions. Parameter sets describing catalyst steric and electronic properties will be derived from physical inorganic characterization data and computational analyses. These parameters will be applied to the development of quantitative selectivity models to guide catalyst optimization for the [4+2]- cycloaddition of unactivated coupling partners. Complementary work in Aim 2 will exploit the olefinic character of cyclopropanes to access homologous metallocyclic intermediates in the development of a unified strategy for iron-catalyzed [2+n]- and [3+n]-cycloaddition reactions with alkene and diene coupling partners. Drawing from these endeavors, an improved understanding of the catalyst?substrate interactions involved in the formation and breakdown of the key metallocyclic intermediate will be leveraged in Aim 3 to enable enantioselective iron-catalyzed cross-[2+2]-cycloaddition reactions of unactivated dienes and internal olefins. Successful realization of these specific aims will afford methods for the stereo- and regiocontrolled synthesis of underexplored sp3-rich motifs for the development of small-molecule therapeutics. This work stands to afford both conceptual and practical advances in the application of base-metal catalysis to the preparation of complex aliphatic scaffolds and is thereby expected to provide a lasting impact in the efforts to improve human health.